AbstractAlzheimer’s disease (AD) is the most common diagnosed dementia. AD courses with a progressive loss of cognitive functions, memory and language. It is characterized by the aggregation of β-amyloid peptides (Aβ) forming extracellular “plaques” and hyperphosphorylated tau protein forming intracellular neurofibrillary “tangles” (NFTs). These changes are accompanied by neuronal loss, microvascular damage and pronounced neuroinflammation.
IL-6 is a pleiotropic cytokine which has an important role in neuroinflammatory processes. It has a complex signaling pathway mediated via three distinct modes. (1) Classic signaling involves the binding of a molecule of IL-6 to a specific membrane receptor (mIL-6R), which activates dimerization of gp130 and subsequent downstream JAK/STAT signaling; (2) in the trans-signaling pathway, IL-6 binds to a soluble form of mIL-6R (sIL-6R) to activate gp130. Due to the ubiquitous expression of gp130, most cells in the body can be stimulated by this process. IL-6 trans-signaling is specifically inhibited by the soluble form of gp130, sgp130. (3) Cluster signaling, which has been described as an exclusive mechanism for the communication between dendritic and T cells. As many of the detrimental effects of IL-6 in the CNS occur via trans-signaling, in this thesis we have characterized the role of IL-6 trans-signaling in AD, by crossing transgenic mice expressing sgp130Fc (specific inhibitor of IL-6 trans-signaling) in astrocytes with two different mouse models of AD, the Tg2576 and the 3xTg-AD mice. The Tg2576 had a more robust AD phenotype what facilitated the identification of the effects of the inhibition of IL-6 trans-signaling, which modulated survival, behavioral traits and spatial learning and memory in a sex-dependent manner. Blocking IL-6 trans-signaling decreased amyloid plaques in cortex and hippocampus and Aβ40 and Aβ42 levels in cortex of Tg2576 female mice. The same trend was also observed in 3xTg-AD females. The changes elicited on gliosis by this blocking were unrelated to the amyloid cascade.
Middle-age obesity is a risk factor for AD and besides, many AD patients have to cope with metabolic alterations and loss of body weight when the disease is already present. Since IL-6 is an important modulator of metabolism and energy balance, the role of IL-6 trans-signaling in metabolism and body weight have also been analyzed in the 3xTg-AD model under control and high-fat diet (HFD) conditions. 3xTg-AD animals presented a hypermetabolic state, which was upregulated by the inhibition of IL-6 trans-signaling in females after HFD, whereas the opposite trend was observed in males; endocrine and metabolic changes were in agreement with these effects. Surprisingly, Aβ levels were diminished after the HFD treatment in comparison with mice fed with a normal chow control diet.
These results suggest that IL-6 trans-signaling is involved in the pathogenesis of AD in these two mouse models; it should be considered as a potential therapeutic target for the creation of new AD treatments.
|Date of Award
|19 Sept 2019
|Juan Hidalgo Pareja (Director) & Juan Hidalgo Pareja (Tutor)